Avalglucosidase alfa is a recombinant human acid α-glucosidase (rhGAA) that provides an exogenous source of GAA. Avalglucosidase alfa is a modification of alglucosidase alfa in which approximately 7 hexamannose structures each containing 2 terminal mannose-6-phosphate (bis-M6P) moieties are conjugated to oxidized sialic acid residues on alglucosidase alfa. Avalglucosidase alfa has a 15-fold increase in mannose-6-phosphate (M6P) moieties compared with alglucosidase alfa. Binding to M6P receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalised and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity to degrade glycogen.
The pharmacokinetics of avalglucosidase alfa was evaluated in a population analysis of 75 LOPD patients aged 16 to 78 years who received 5 to 20 mg/kg of avalglucosidase alfa every other week.
The pharmacokinetics of avalglucosidase alfa was characterized in 16 patients aged 1 to 12 years who were treated with avalglucosidase alfa, which included 6 patients treated with 20 mg/kg and 10 patients treated with 40 mg/kg doses every other week. All patients were treatment-experienced.
In LOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week, the mean Cmax and mean AUC2W were 273 µg/mL (24%) and 1220 µg∙h/ml (29%), respectively.
In IOPD patients, for a 4-hour IV infusion of 20 mg/kg every other week and 7-hour IV infusion for 40 mg/kg every other week, the mean Cmax ranged from 175 to 189 μg/ml for the 20 mg/kg dose and 205 to 403 µg/ml for 40 mg/kg dose. The mean AUC2W ranged from 805 to 923 μg∙hr/ml for the 20 mg/kg dose and 1720 to 2630 μg∙hr/ml for 40 mg/kg dose.
In LOPD patients, the typical population PK model predicted central compartment volume of distribution of avalglucosidase alfa was 3.4 L.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, the mean volume of distribution at steady state ranged between 3.5 to 5.4 L.
In LOPD patients, the typical population PK model predicted linear clearance was 0.87 L/h. Following 20 mg/kg every other week, the mean plasma elimination half-life was 1.55 hours.
In IOPD patients treated with avalglucosidase alfa 20 mg/kg and 40 mg/kg every other week, mean plasma clearance ranged from 0.53 to 0.70 L/h, and mean plasma elimination half-life from 0.60 to 1.19 hours.
The exposure to avalglucosidase alfa increased in a dose-proportional manner between 5 to 20 mg/kg in LOPD patients and between 20 and 40 mg/kg in IOPD patients. No accumulation was observed following every other week dosing.
In the study 1, EFC14028/COMET, 96.1% (49 of 51 patients) receiving avalglucosidase alfa developed treatment-emergent ADA. No clear trend of ADA impact on PK was observed.
Population pharmacokinetic analyses in LOPD patients showed that body weight, age, and gender did not meaningfully influence the pharmacokinetics of avalglucosidase alfa.
The pharmacokinetics of avalglucosidase alfa has not been studied in patients with hepatic impairment.
No formal study of the effect of renal impairment on the pharmacokinetics of avalglucosidase alfa was conducted. On the basis of a population pharmacokinetic analysis of data from 75 LOPD patients receiving 20 mg/kg, including 6 patients with mild renal impairment (glomerular filtration rate: 60 to 89 ml/min; at baseline), no relevant effect of renal impairment on avalglucosidase alfa exposure was observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeat dose toxicity that included safety pharmacology endpoints.
Avalglucosidase alfa caused no adverse effects in a combined male and female fertility study in mice up to 50 mg/kg IV every other day (9.4 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD).
In an embryo-foetal toxicity study in mice, administration of avalglucosidase at the highest dose of 50 mg/kg/day (17 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD) produced increased post-implantation loss and mean number of late resorptions. No effects were seen at 20 mg/kg/day (4.8 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD). Avalglucosidase alfa does not cross the placenta in mice, suggesting that the embryo-foetal effects at 50 mg/kg/day were related to maternal toxicity from the immunologic response. No malformations or developmental variations were observed.
No adverse effects were observed in an embryo-foetal toxicity study in rabbits administered avalglucosidase alfa up to 100 mg/kg/day IV (91 times the human steady-state AUC at the recommended biweekly dose of 20 mg/kg for patients with LOPD).
There were no adverse effects in a pre- and post-natal developmental toxicity study in mice following administration of avalglucosidase alfa once every other day. The NOAEL for reproduction in the dams and for viability and growth in the offspring was 50 mg/kg every other day IV.
In juvenile mice, avalglucosidase alfa was generally well tolerated following administration for 9 weeks at doses up to 100 mg/kg every other week IV (~2 to 5 times the human steady-state AUC at the recommended biweekly dose of 40 mg/kg for patients with IOPD). However, the highest dose tested in juvenile animals is not enough to discard a potential risk for IOPD patients at 40 mg/kg based on exposure margin.
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